Project Summary/Abstract ?Entorhinal-Hippocampal Circuit Dysfunction in AD Mice? (3 R01 AG050425-03) Spatial memory impairment and disorientation are a common problem associated with aging and they are often one of the first symptoms of mild cognitive impairment and Alzheimer's disease (AD). Understanding the properties of cells involved in the formation of spatial memory in mouse models with early AD pathology will enhance our understanding of the earliest forms of cognitive decline in AD. The cells known to be important in spatial memory are place cells of the hippocampus (HPC) and grid and head direction cells of the entorhinal cortex (EC). We propose to simultaneously record the electrophysiological properties of grid and place cells using 128-channel electrode recordings from 3 regions of the entorhinal cortex-hippocampal (EC-HPC) circuit in AD mice. We will then analyze the large- scale electrophysiological data and measure synaptic plasticity using a spike-timing dependent plasticity (STDP) model. Predictions from this model will be used as a guide to adjust spike timing in neurons, either enhancing or suppressing the synaptic strength of cell populations in affected regions of the EC- HPC, using optogenetic modulation. We anticipate that this will allow us to correct the spatial impairment deficits. To recapitulate the spatial orientation impairments seen in early-stage AD patients, behaviorally equivalent tasks in mice such as morphing open fields, spatial novel object recognition task and T-maze alternation tasks will be applied. These tasks have been chosen specifically to study the functioning of EC-HPC circuit neurons (CA1, CA3, dentate gyrus, lateral and medial entorhinal cortex) that get activated in relevant behavioral modes. The proposal brings together diverse fields (electrophysiology, molecular neuroscience and computational neuroscience) applying large-scale recording techniques simultaneously across multiple brain regions to develop analytical and predictive computational tests to interrogate and restore function in an important circuit that is dysfunctional in Alzheimer's disease. In this supplement, we propose to apply new technological advances in optical imaging to record neuronal activity patterns from large-scale neuronal populations in the EC of mice possessing AD pathology. In addition to disturbances in firing rates, we can also analyze the effect of AD pathology on grid and head-direction cells, which contributes to the aims of the parent grant.